The
Effects of Alcohol on Physiological Processes and Biological Development

Adolescence
is a period of rapid growth and physical change; a central question is whether
consuming alcohol during this stage can disrupt development in ways that have
long-term consequences. In general, the existing evidence suggests that adolescents
rarely exhibit the more severe chronic disorders associated with alcohol dependence
such as liver cirrhosis, hepatitis, gastritis, and pancreatitis. Adolescents
who drink heavily, however, may experience some adverse effects on the liver,
bone, growth, and endocrine development. Evidence also is mounting, at least
in animal models, that early alcohol use may have detrimental effects on the
developing brain, perhaps leading to problems with cognition later in life.
This article summarizes the physiological effects of alcohol on adolescents,
including a look at the long-term behavioral and physiological consequences
of early drinking.
Key words: underage drinking; binge drinking; AODU (alcohol and other drug use);
adolescence; growth and development; puberty; physiological AODE (alcohol and
other drug effects); psychological AODE; chronic AODE; brain; liver; bone; reproductive
system; sexual maturation; long-term AOD (alcohol and other drug) use; animal
studies

OVERVIEW

The damage that long-term
heavy alcohol consumption can do to the health of adults is well documented.
Some research suggests that, even over the shorter time frame of adolescence,
drinking alcohol can harm the liver, bones, endocrine system, and brain, and
interfere with growth. Adolescence is a period of rapid growth and physical
change; a central question is whether consuming alcohol during this stage can
disrupt development in ways that have long-term consequences.

Liver disease is a common
consequence of heavy drinking. More severe alcohol-related liver disease typically
reflects years of heavy alcohol use. However, elevated liver enzymes that are
markers of harm have been found in adolescents with alcohol use disorders and
in overweight adolescents who consume more modest amounts of alcohol.

During puberty, accelerating
cascades of growth factors and sex hormones set off sexual maturation, growth
in stature and muscle mass, and bone development. Studies in humans have found
that alcohol can lower the levels of growth and sex hormones in both adolescent
boys and girls. In animals, alcohol has been found to disrupt the interaction
between the brain, the pituitary gland (which regulates secretion of sex hormones),
and the ovaries, as well as systems within the ovaries that are involved in
regulating sex hormones. In adolescent male animals, both short- and long-term
alcohol administration suppresses testosterone; alcohol use also alters growth
hormone levels, the effects of which differ with age.

Studies on alcohol and adolescent
bone development are limited. In studies of male and female rats, chronic alcohol
consumption (an alcohol diet) for the length of adolescence was found to stunt
limb growth. One study found that feeding female rats alcohol in a way that
mimics binge drinking resulted in either increases in bone length and density
or in no change with more frequent bingeing. In human adolescent males but not
females, studies have found that alcohol consumption decreases bone density.

The brain also is changing
during adolescence. Adolescents tend to drink larger quantities on each drinking
occasion than adults; this may in part be because adolescents are less sensitive
to some of the unpleasant effects of intoxication. However, research suggests
that adolescents may be more sensitive to some of alcohol’s harmful effects
on brain function. Studies in rats found that alcohol impairs the ability of
adolescent animals more than adult animals to learn a task that requires spatial
memory. Research also suggests a mechanism for this effect; in adolescents more
than adults, alcohol inhibits the process in which, with repeated experience,
nerve impulses travel more easily across the gap between nerve cells (i.e.,
neurons) involved in the task being learned. The reasons for these differences
in sensitivity to alcohol remain unclear.

Research also has found
differences in the effects of bingelike drinking in adolescents compared with
adults. Normally, as people age from adolescence to adulthood, they become more
sensitive to alcohol’s effects on motor coordination. In one study, however,
adolescent rats exposed to intermittent alcohol never developed this increased
sensitivity. Other studies in both human subjects and animals suggest that the
adolescent brain may be more vulnerable than the adult brain to chronic alcohol
abuse.

Young people who reported
beginning to drink at age 14 or younger also were four times more likely to
report meeting the criteria for alcohol dependence at some point in their lives
than were those who began drinking after age 21. Although it is possible that
early alcohol use may be a marker for those who are at risk for alcohol disorders,
an important question is whether early alcohol exposure may alter neurodevelopment
in a way that increases risk of later abuse. Research in rats has found that
prenatal or early postnatal exposure to alcohol results in a greater preference
for the odor and consumption of alcohol later in life. Social experiences associated
with youthful drinking also may influence drinking later in life. Additional
research is needed to resolve the question of whether and how early alcohol
exposure might contribute to drinking problems years down the road.

ALCOHOL’S EFFECTS
ON THE LIVER, THE NEUROENDOCRINE SYSTEM, AND BONE

The medical consequences
of chronic alcohol abuse and dependence have been well documented in adults.
They include liver disease, lung disease, compromised immune function, endocrine
disorders, and brain changes. Investigations of the health problems associated
with adolescent alcohol abuse are sparse and rely mainly on self-report (see
Clark et al. 2001; Aarons et al. 1999; Brown and Tapert 2004). In general, the
existing evidence suggests that adolescents rarely exhibit the more severe chronic
disorders associated with alcohol dependence, such as liver cirrhosis, hepatitis,
gastritis, and pancreatitis. However, more research is needed to determine whether
severe alcohol-induced organ damage is strictly a cumulative process that begins
in adolescence and culminates in adulthood as a result of long-term chronic
heavy drinking or whether serious alcohol-related health problems can emerge
during the teenage years. The few studies available indicate that adolescents
who drink heavily experience adverse effects on the liver, bones, growth, and
endocrine development, as summarized below. The effects of chronic alcohol consumption
on the adolescent brain are discussed in the section “Long-Term Behavioral
and Physiological Conse quences of Early Drinking.”

Liver Effects

Elevated liver enzymes have
been found in some adolescents who drink alcohol. Clark and colleagues (2001)
found that adolescent alcohol use disorders were associated with higher gamma-glutamyl
transpeptidase (GGT) and alanine amino transferase (ALT). Moreover, young drinkers
who also are overweight or obese exhibit elevated levels of serum ALT with even
modest amounts of alcohol intake (Strauss et al. 2000).

Growth and Endocrine
Effects

In general, there has been
a gradual decline in the onset of female puberty over the last century, at least
when puberty is defined by age at menarche (Tanner 1989). Whether initiation
of female puberty is continuing to decline and at what rate are the subjects
of some debate (Lee et al. 2001; Herman-Giddens et al. 1997). Much less information
exists on pubertal development in males because of the greater difficulty in
assessing developmental milestones. However, a recent study comparing data from
two national surveys, one conducted between 1988 and 1994 and the other between
1963 and 1970, found that American boys from the later generation had earlier
onset of some pubertal stages as measured by standard Tanner staging (Herman-Giddens
et al. 2001; Karpati et al. 2002). Perhaps not surprisingly, early puberty—especially
among girls—is associated with early use of alcohol, tobacco, and other
drugs (Wilson et al. 1994; Dick et al. 2000). In addition, alcohol use in early
maturing adolescents has implications for normal growth and neuroendocrine development.

In both males and females,
puberty is a period of activation of the hypothalamic-pituitary-gonadal (HPG)
axis. Pulsatile secretion of gonadotrophin-releasing hormone (GnRH) from the
hypothalamus stimulates pituitary secretion of follicle-stimulating hormone
(FSH) and luteinizing hormone (LH) pulses, followed by marked increases in gonadal
sex steroid output (estrogen and testosterone), which in turn increases growth
hormone (GH) and insulin-like growth factor-1 (IGF-1) production (see Mauras
et al. 1996). Data from several studies suggest that both androgens and estrogens
stimulate GH production, but that estrogen controls the feedback mechanism of
GH production during puberty even in males (Mauras et al. 1996; Dees et al.
2001). The increase in these hormones not only promotes maturation of the gonads
but also affects growth, muscle mass, and mineralization of the skeleton. Thus,
alcohol consumed during rapid development (i.e., prior to or during puberty)
has the potential to disrupt normal growth and endocrine development through
its effects on the hypothalamus, the pituitary gland, and the various target
organs such as the ovaries and testes.

Most human and animal research
on alcohol and endocrine development has been conducted in females, but the
limited data on both genders suggest that alcohol can have substantial effects
on neuroendocrine function (see Dees et al. 2001; Emanuele et al. 1998; Emanuele
et al. 2002a,b). Human studies have found that alcohol ingestion can lower estrogen
levels in adolescent girls (Block et al. 1993) and lower both LH and testosterone
levels in midpubertal boys (Diamond et al. 1986; Frias et al. 2000a). In both
genders, acute alcohol intoxication produces a decrease in GH levels without
significant change in either IGF-1 or insulin-like growth factor binding protein-3
(IGFBP3) (Frias et al. 2000b).

In female rats, alcohol
has been shown to suppress the secretion of specific female reproductive hormones,
thereby delaying the onset of puberty (see Dees et al. 2001 and Emanuele et
al). Dees and colleagues (2000) found that immature female rhesus macaques exposed
daily to alcohol (2 g/kg via nasogastric tube) exhibit lower levels of GH, FSH,
LH, estradiol (E2), and IGF-1 (but not FSH or Leptin) compared with
control subjects. Moreover, even though there was no effect on age of menarche
in these animals, the interval between subsequent menstruations was lengthened,
thereby interfering with the development of regular monthly cycles. Additional
studies in rats have found that alcohol interferes with intraovarian systems,
including IGF-1 and IGF-1 receptors; the nitric oxide (NO) system (Dees et al.
2001; Srivastava et al. 2001a), and the steroidogenic acute regulatory
protein (StAR) (Srivastava et al. 2001b), all of which combine to decrease
estradiol secretion. Thus, alcohol not only disrupts the interaction between
the brain, pituitary gland, and ovaries, it also directly impairs the regulatory
systems within the ovaries (see Dees et al. 2001 for review).

Thus, the data so far indicate
that females who consume alcohol during early adolescence may be at risk for
adverse effects on maturation of the reproductive system. Although in males
the long-term effects of alcohol on reproductive function are unclear, the fact
that GH as well as testosterone and/or estrogen levels are altered by alcohol
in both genders may have serious implications for normal development because
these hormones play a critical role in organ maturation during this stage of
development.

Bone Density
and Growth Effects

Only a handful of studies
have examined the effects of adolescent drinking on bone development, with the
most informative data thus far coming from animal research. Male rats chronically
fed an alcohol liquid diet for 60 days encompassing the adolescent period (postnatal
days 35 to 90) display limb length reduction and reduced metaphyseal and cortical
bone growth in the limbs (Wezeman et al. 1999). These skeletal effects may be
mediated through a reduction in osteoblast formation, which is associated with
a decline in testosterone but not IGF-1. In addition, with abstinence, normal
bone metabolism is not completely restored. Similarly, in female rats, Sampson
and colleagues (Sampson et al. 1996; Sampson and Spears 1999) found that chronic
alcohol consumption (4 weeks on an ethanol liquid diet) produces decreased limb
length and reductions in cortical and cancellous bone, which are not fully reversed
following cessation of drinking. Interestingly, female adolescent animals administered
a binge model of drinking (i.e., 5 percent alcohol by gavage for either 2 or
5 consecutive days per week) show increased bone length, weight, and density,
or no change, respectively (Sampson et al. 1999). Human studies indicate an
inverse relationship between alcohol consumption and bone mineral density in
adolescent males, but not females (Fehily et al. 1992; Neville et al. 2002;
Elgan et al. 2002; Fujita et al. 1999). However, more studies are needed in
humans and animals to get a clearer picture of alcohol’s effects on bone
growth in adolescents, particularly with respect to dose and pattern of consumption.

A Snapshot of Findings
on Alcohol’s Physiological Effects in Adolescent Humans & Animals

Findings

Study

On the Liver

In humans

Levels of enzymes
that indicate liver damage are higher in adolescents with alcohol use
disorders

And to more damage
to the frontal-anterior cortical regions of the brain than are produced
in adult rats.

Crews et al. 2000

Prolonged alcohol
exposure during adolescence produces:

Neurophysiological
changes in the response to alcohol challenge and in the tolerance to
alcohol’s sedative effects;

Enhanced expression
of withdrawal behaviors; and

Long-lasting neurophysiological
effects in the cortex and hippocampus.

Slawecki et al. 2001;
Slawecki 2002; Slawecki and Roth 2004

LONG-TERM BEHAVIORAL AND
PHYSIOLOGICAL CONSEQUENCES OF EARLY DRINKING

Although increased tolerance
to alcohol’s sedative effects may enable greater intake in adolescents,
repeated exposure to alcohol may produce increased sensitivity to alcohol’s
harmful effects. Studies in rats show that ethanol-induced inhibition of synaptic
potentials mediated by N-methyl-D-aspartate (NMDA) and long-term potentiation
(LTP) is greater in adolescents than in adults (Swartzwelder et al. 1995a,b;
see White and Swartzwelder 2005 for review). Initially, the developmental sensitivity
of NMDA currents to alcohol was observed in the hippocampus, but more recently
this effect was found outside the hippocampus in pyramidal cells in the posterior
cingulate cortex (Li et al. 2002). Behaviorally, adolescent rats show greater
impairment than adults in acquisition of a spatial memory task after acute ethanol
exposure (Markwiese et al. 1998) in support of greater LTP sensitivity to alcohol
in adolescents. Behavioral and neurobiological mechanisms for the ontogenetic
differences in alcohol tolerance and sensitivity are unclear, as is the relationship
between differential sensitivity to ethanol and onset of alcohol abuse and alcoholism.

Binge alcohol exposure (i.e.,
chronic intermittent exposure to high alcohol doses) in rats during adolescence
produces long-lasting changes in memory function (White et al. 2000) and interferes
with the normal development of sensitivity to alcohol-induced motor impairments
(White et al. 2002). In addition, prolonged alcohol exposure during adolescence,
but not adulthood, produces alterations in neurophysiological response to ethanol
challenge, tolerance to the sedative effects of ethanol, enhanced expression
of withdrawal-related behavior, and long-lasting neurophysiological changes
in the cortex and hippocampus in rats (Slawecki et al. 2001; Slawecki 2002;
Slawecki and Roth 2004). Further more, chronic ethanol treatment in rats may
lead to increased NMDA-mediated neurotoxicity, which could be exacerbated by
repeated withdrawals (Hunt 1993). Consistent with this hypothesis is the finding
that severity of alcohol and drug withdrawal symptoms may be a powerful marker
of neuropsychological impairments in detoxified older human adolescents and
young adults (Brown et al. 2000; Tapert and Brown 1999; Tapert et al. 2002).
Moreover, one recent study found reduced hippocampal volumes in human adolescents
with a history of alcohol abuse/dependence disorder (De Bellis et al. 2000),
and another preliminary investigation of alcohol-abusing teenagers observed
subtle white-matter microstructure abnormalities in the corpus callosum (Tapert
et al. 2003), which may be a precursor of more severe damage produced by long-term
chronic drinking (Pfefferbaum and Sullivan 2002). Juvenile rats exposed to heavy
bingelike episodes of ethanol have greater damage than adults in frontal-anterior
cortical regions, including the olfactory frontal cortex, anterior perirhinal,
and piriform cortex (Crews et al. 2000). Thus, the immature brain may be more
susceptible to binge ethanol-induced neurotoxicity, although the mechanisms
are unknown.

Because teenagers are likely
to engage in binge drinking, it is important to study the effects of chronic
binge patterns of ethanol exposure on brain structure, neurochemistry, and cognitive
functioning. Care must be taken in extrapolating from the described animal studies
to the binge-drinking adolescent. Because binge drinking does not usually entail
withdrawal, it is important to distinguish between damage caused by the alcohol
itself and that caused by repeated withdrawals. In addition, primate models
may be a better choice for studying the long-term consequences of alcohol exposure
because of primates’ prolonged adolescent period, which allows extensive
manipulation of different types and lengths of exposure. These models, coupled
with new neuroanatomical and neuroimaging techniques, offer a unique opportunity
to study the brain changes associated with adolescent drinking and determine
whether adolescent brains are able to recover more easily because of greater
plasticity.

Early Exposure
as a Predictor of Later Alcohol Abuse

Early exposure to alcohol—at
or before age 14—is strongly associated with later alcohol abuse and dependence
(Grant and Dawson 1998). Two possible explanations for this effect are obvious.
First, early alcohol use may simply be a marker for later alcohol abuse rather
than a causative factor. A good deal of evidence indicates that at least one
behavioral factor, behavioral undercontrol, is measurable very early in life
and is a consistently robust predictor of earlier alcohol use as well as of
elevated risk for later alcohol use disorder (NIAAA 2000; Zucker and Wong 2005;
Caspi et al. 1996).

Second, it is possible that
alcohol exposure during adolescence actually may alter neurodevelopmental processes
in such a way that the likelihood of later abuse is increased. For example,
alcohol use could promote rewiring or alter normal maturation and pruning within
the nervous system. Ample evidence exists that exposing rats to low or moderate
doses of alcohol during the prenatal or early postnatal period yields a greater
preference for ethanol’s odor and its consumption later in life (Abate
et al. 2000; Honey and Galef 2003; see Molina et al. 1999 and Spear and Molina
2001 for reviews). The young rat’s response to alcohol also is mediated
by social factors such as maternal interactions and/or nursing from an intoxicated
dam (e.g., Hunt et al. 2001; Pepino et al. 2001, 2002; Spear and Molina 2001).
Recent evidence shows that prior nursing experience from an ethanol-intoxicated
dam heightens ethanol consumption in infant and adolescent rats (Ponce et al.
2004; Pepino et al. 2004). In contrast, relatively few reports using animal
models to study the effects of adolescent alcohol exposure on later alcohol
consumption exist, and the results are conflicting (see Spear and Varlinskaya
2005). Yet, as is the case with younger animals, social experiences associated
with adolescent drinking may influence future drinking behaviors (Hunt et al.
2001; Varlinskaya and Spear 2002). More studies are needed, however, to explore
whether a causal relationship between early chronic exposure to alcohol and
later alcohol problems exists, as well as to discover the underlying mechanisms
for this effect. Nonhuman primates, because of their extended adolescent period,
offer a good opportunity to study the effects of early exposure to alcohol.

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from Current Research. Bethesda, MD: Dept. of Health and Human Services,
NIAAA, 2000. pp. 28–53. Available online at: http://pubs.niaaa.nih.gov/publications/10report/intro.pdf.

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Varlinskaya, E.I., and Spear,
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